Biology subjects

Saijo, K.

Publications and source records attributed to Saijo, K..

3 recordsLinked to original sources

bioRxiv2020

Cytoskeletal tension forces mitohormesis

Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. However, the physical characteristics of the extracellular matrix are also altered in cancer and in aging tissues. We demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via SLC9A1-dependent ion exchange and HSF1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/979583v3_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1ecdaceorg.highwire.dtl.DTLVardef@1112c32org.highwire.dtl.DTLVardef@6c99a1org.highwire.dtl.DTLVardef@1da1e5f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2019

Phf15, a novel transcriptional repressor regulating inflammation in mouse microglia

AimExcessive microglial inflammation has emerged as a key player in mediating the effects of aging and neurodegeneration on brain dysfunction. Thus, there is great interest in discovering transcriptional repressors that can control this process. We aimed to examine whether Phf15--one of the top differentially expressed genes in microglia during aging in humans--could regulate transcription of pro-inflammatory mediators in microglia. MethodsRT-qPCR was used to assess Phf15 mRNA expression in mouse brain during aging. Loss-of-function (shRNA-mediated knockdown (KD) and CRISPR/Cas9-mediated knockout (KO) of Phf15) and gain-of-function (retroviral overexpression (OE) of murine Phf15 cDNA) studies in a murine microglial cell line (SIM-A9) followed by immune activation with lipopolysaccharide (LPS) were used to determine the effect of Phf15 on pro-inflammatory factor (Tnf, Il-1{beta}, Nos2) mRNA expression. RNA-sequencing was used to determine global transcriptional changes after Phf15 knockout under basal conditions and after LPS stimulation. ResultsPhf15 expression increases in mouse brain during aging, similar to humans. KD, KO and OE studies determined that Phf15 represses mRNA expression levels of pro-inflammatory mediators such as Tnf, Il-1{beta} and Nos2. Global transcriptional changes after Phf15 KO showed that Phf15 specifically represses genes related to the antiviral (type I interferon) response and cytokine production in microglia. ConclusionWe provide the first evidence that Phf15 is an important transcriptional repressor of microglial inflammation, regulating the antiviral response and pro-inflammatory cytokine production. Importantly, Phf15 regulates both basal and signal-dependent activation and controls the magnitude and duration of the microglial inflammatory response.

neuroscience↗

bioRxiv2019

Defective cell death of distinct microglial subsets contributes to ADHD-like behavior in mice

Microglia are resident immune cells in the central nervous system that play essential roles to maintain homeostasis and neuronal function. Microglia are heterogeneous cells but the mechanisms by which they contribute to normal brain development remain unclear. Here,we show that microglia in the developing striatum and thalamus undergo pyroptosis,a type of lytic cell death that occurs as a result of Caspase-1 (CASP1) activation downstream of inflammasomes. We observe that pyroptosis occurs in a spatiotemporally regulated and Casp1-dependent manner during fetal brain development. Mice lacking Casp1 or the inflammasome regulating molecules, NLRP3, IL-1R, and Gasdermin D exhibit behavior changes characterized by hyperactivity, inattention, and impulsivity that are similar to attention-deficit/hyperactivity disorder (ADHD). Furthermore, re-expression of Casp1 in Cx3cr1+ cells including microglia restores normal behavior and cell death. We demonstrate that injection of an NLRP3 inhibitor into pregnant wild-type mice is sufficient to induce ADHD-like behaviors in offspring. These data suggest that microglial inflammasome activation and pyroptosis are essential for normal brain development and that genetic and pharmacological disruptions in this pathway may represent new ADHD risk factors.

neuroscience↗